Abstract & Commentary
Synopsis: There is currently no test which reliably assists in forecasting the duration of hormone dependence in patients receiving androgen ablative therapy for metastatic prostate cancer or for biochemical failure following attempted cure. Thus, predictions of the duration until development of hormone refractory disease are conjecture with little basis in science. Elimination of some or all of this uncertainty would benefit the clinical decision-making process. This study from Case Western Reserve performed a retrospective review of their patients maintained on androgen ablative therapy, and concluded that body mass index (BMI) and history of pathological fracture were novel, statistically significant, predictors of the duration of androgen independence and survival, respectively.
Source: Oefelein MG, et al. Urology. 2002;60:120-124.
Oefelein and colleagues performed a retrospective analysis of 184 consecutive prostate cancer patients who required androgen ablative therapy from 1986. There were 122 patients on monotherapy, 58 on total androgen suppression, and 4 who underwent orchiectomy. Median age was 72 years (range, 49-90), and median pretreatment PSA was 32 (range, 1.8-6033). One hundred twenty-six patients were white, 53 were African-American, and 5 were other. Reasons for initiation of androgen suppression were metastases to bone or lymph nodes (62%), or biochemical failure posttreatment (38%). Time to androgen independence was measured from the start of androgen suppression to the date of the first of 3 rising PSA values taken consecutively at 3-6 month intervals.
Eighty five patients (46%) became hormone refractory during the study period. Median overall survival for the entire group was 123 months. Median overall survival for patients started on therapy for a positive bone scan was 55%, and 89% for patients started on therapy for biochemical failures. Median time to development of hormone refractory disease was 44 months. It was 24 months for patients with bone metastases and 63 months for biochemical failure patients (P = .000001).
Significant factors for the development of hormone independent disease on univariate analysis were PSA nadir > 1, > 3 months to PSA nadir, pretreatment PSA > 50, > 44 months of androgen suppression, bone metastases, and BMI > 27 kg/m2. Factors that did not reach significance were race, Gleason score, primary treatment, and history of pathologic fracture. Multivariate analysis revealed several factors that were predictive of the duration to androgen independence and survival, including PSA nadir > 1, > 3 months to PSA nadir, bone metastases, and BMI > 27 kg/m2. In terms of which patients did the best, Oefelein et al found that slender patients who started with a biochemical failure and reached a PSA nadir in < 3 months had a median androgen dependent interval of 132 months, in comparison to heavy patients with bone metastases who never reached a PSA nadir, where the interval to androgen independence was only 15 months (P = .00001). Multivariate analysis evaluating factors predictive for overall survival found that bone metastases, pretreatment PSA, and history of pathologic fracture were significant (P < .05).
Oefelein et al concluded that BMI was a potentially important predictor of time to androgen independence, and that pathologic fractures were poor prognostic factors for overall survival. They pointed out that these 2 prognostic factors have not been previously recognized as clinically important in the setting of response to androgen ablation. A nomogram plugging in their institutional results, with + bone metastases on the y-axis and time to PSA nadir < 3 months vs. > 3 months on the x-axis, was provided and showed statistically significant differences in median time to androgen independence. Oefelein et al stated that prolonged, "possibly curative control" with androgen ablation exists in a subset of patients.
Comment by Edward J. Kaplan, MD
Surprisingly little is known about the optimal time to initiate androgen suppressive therapy, whether such therapy should be maintained on a continuous basis, or how one predicts the durability of response to androgen ablation. The intuitive notion that measurable disease, as in a positive bone scan or a pathologic fracture, or a high starting PSA, is worse is not surprising. It is also not surprising that patients whose disease is responsive to androgen ablation as reflected by a rapidly achieved and low nadir do better. Undetectable nadir PSA was also found to be significantly related to time to androgen independence by Benaim and colleagues from the University of Texas.1
Oefelein et al identified BMI as a new and potentially useful indicator of the duration of androgen independence for patients on ablative therapy. They referred to earlier work by others pointing to increased peripheral conversion of testosterone to estrogen in obese men as a risk factor for development of prostate cancer, and indicated that the same mechanism may be at work in their findings with BMI.
There were too few patients in the study to evaluate whether monotherapy was any more or less effective than combined androgen ablative therapy. Since all patients received continuous therapy, any contribution by intermittent androgen ablation was not evaluable. Oefelein et al, while postulating that BMI may be important based on serum testosterone levels, did not suggest that they were interested in measuring pretreatment serum testosterone in their patients. Perhaps focusing on percent body fat might be more to the point than BMI, since that seems to be where the conversion of testosterone to estrogen takes place. Along these lines, Vollmer et al analyzed data from 2 CALGB trials on hormone refractory prostate cancer patients, and found that patient weight was significantly related to survival.2 Another very interesting finding by George et al from Dana Farber, also based on CALGB data, was that plasma vascular endothelial growth factor (VEGF) levels are significantly elevated in patients with hormone independent disease and inversely correlated with survival (P =. 002).3
Since BMI can be changed through dietary control, it is of interest to know whether BMI, weight, or percent body fat can alter a metastatic prostate cancer patient’s prognosis. Furthermore, fat is a very metabolic tissue, and it likely has something to do with one’s VEGF levels. For now, the nomogram shown by Oelefein et al may be useful in formulating treatment planning strategies when used in conjunction with other known prognostic factors such as pretreatment PSA.
Dr. Kaplan is Acting Chairman, Department of Radiation Oncology, Cleveland Clinic Florida, Ft. Lauderdale, FL; Medical Director, Boca Raton Radiation Therapy Regional Center, Deerfield Beach, FL.
References
1. Benaim EA, et al. Urology. 2002;59:73-78.
2. Vollmer RT, et al. Clin Cancer Res. 1999;5:831-837.
3. George DJ, et al. Clin Cancer Res. 2001;7:1932-1936.
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